Gut microbiome-mediated modulation of hepatic cytochrome P450 and P-glycoprotein: impact of butyrate and fructo-oligosaccharide-inulin
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Date
2020-04-26
Authors
Walsh, Jacinta
Gheorghe, Cassandra Elise
Lyte, Joshua M.
van de Wouw, Marcel
Boehme, Marcus
Dinan, Timothy G.
Cryan, John F.
Griffin, Brendan T.
Clarke, Gerard
Hyland, Niall P.
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Publisher
Wiley
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Abstract
Objectives: Our objective was to demonstrate microbial regulation of hepatic genes implicated in drug metabolism and transport using germ‐free (GF) mice and to explore the impact of a microbial metabolite, butyrate, and a prebiotic dietary intervention on hepatic gene expression in mice. Methods: Using reverse‐transcriptase PCR, we investigated cytochrome P450 (CYP) and multidrug‐resistance protein 1 (MDR1) expression in conventional, GF and colonised GF mice. To investigate the effects of butyrate, sodium butyrate (3 g/l) was administered for 21 days to conventional or GF mice. In the prebiotic study, young adult and middle‐aged mice received diet enriched with 10% fructo‐oligosaccharide (FOS)‐inulin for 14 weeks. Key findings: Colonisation of GF animals normalised expression of Cyp3a11 and Mdr1b to conventional levels. Butyrate upregulated Cyp2b10 in conventional mice (P < 0.05) but overall did not induce widespread changes in hepatic genes. FOS‐inulin increased Cyp3a13 expression and had the opposite effect on Mdr1a expression in young adult mice (P < 0.05). Age, on the other hand, influenced the prebiotic effect on Cyp2a4 expression (P < 0.01). Conclusion: The expression of hepatic genes implicated in drug metabolism and transport displays sensitivity to the microbiome, microbiome‐derived metabolites and a microbial‐targeted intervention. Our study may provide the impetus to explore microbiota‐targeted interventions in normalising host metabolic activity and reducing inter‐individual variability in drug pharmacokinetics.
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Keywords
Cytochrome , Hepatic , Metabolism , Microbiome , Transporter
Citation
Walsh, J., Gheorghe, C.E., Lyte, J.M., van de Wouw, M., Boehme, M., Dinan, T.G., Cryan, J.F., Griffin, B.T., Clarke, G. and Hyland, N.P. (2020) 'Gut microbiome‐mediated modulation of hepatic cytochrome P450 and P‐glycoprotein: impact of butyrate and fructo‐oligosaccharide‐inulin', Journal of Pharmacy and Pharmacology, doi: 10.1111/jphp.13276
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© 2020 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology. This is the peer reviewed version of the following article: (2020), Gut microbiome‐mediated modulation of hepatic cytochrome P450 and P‐glycoprotein: impact of butyrate and fructo‐oligosaccharide‐inulin. J Pharm Pharmacol., which has been published in final form at https://doi.org/10.1111/jphp.13276 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.